Indole derivatives as 5-α-reductase-1-inhibitors

ABSTRACT

A compound of formula (I): ##STR1## and the pharmaceutically acceptable base salts thereof, wherein: R is CO 2  R 12  where R 12  is H or a biolabile ester-forming group, or R is tetrazol-5-yl, and either (a) R 1  is ##STR2## and R 2  is F, Cl, Br, I, CH 3  or CF 3 , or (b) R 1  is C 3  -C 6  alkyl and R 2  is C 2  -C 4  alkyl, useful as steroid 5-α-reductase inhibitors.

This is a 371 of PCT/EPA4/02563, filed Aug. 2, 1994.

This invention relates to indole derivatives which have steroid5α-reductase inhibitory activity.

More particularly this Invention relates to certain 3-(2,2-disubstituted-1,3-benzodioxolan-5-yl)carbonyl!2-methylindolederivatives, their preparation and their use as testosterone5α-reductase inhibitors.

The androgen class of steroidal hormones is responsible for thedifference In the physical characteristics of males and females. Of allthe organs that produce androgens, the testes produce these hormones inthe greatest amounts. Over-production of these hormones in the bodyresults in many undesirable physical manifestations and disease states,e.g. acne vulgaris, alopecia, seborrhoea, female hirsutism, benignprostatic hypertrophy and male pattern baldness.

The principal androgen secreted by the testes is testosterone and it isthe primary androgen present in male plasma. The principal mediators ofandrogenic activity in certain organs such as the prostate and sebaceousglands are the 5α-reduced androgens. Testosterone is therefore theprohormone of 5α-dihydrotestosterone (DHT) which is formed locally inthe above organs by the action of testosterone 5α-reductase. Thepresence of elevated levels of dihydrotestosterone in many diseasestates has therefore focussed attention on the synthesis of testosterone5α-reductase inhibitors.

The enzyme 5α-reductase mediates the conversion of testosterone to themore potent androgen DHT locally, in the target organ. It has beenpostulated, and demonstrated, that inhibitors of 50α-reductase shouldblock the formation of DHT and bring about amelioration of the aboveundesirable physiological conditions. Testosterone 5α-reductaseinhibitors may also be useful in the treatment of human prostateadenocarcinomas. Recently, two 5-α-reductase isozymes (designated types1 and 2) have been described in humans, Andersson et al., Proc. Natl.Acad. Sci. U.S.A., 87, 3640-3644 (1990; Andersson et al., Nature, 354,159-161 (1991). In addition to certain structural differences, the twoisozymes exhibit some differences with respect to their biochemicalproperties, expression patterns, genetics, and pharmacology, Anderssonet al., Nature, 354, 159-161 (1991); Jenkins, et al., Journal ofClinical Investigation,89, 293-300 (1992). Further elucidation of theroles that the two 5α-reductase isozymes play In androgen action iscurrently the subject of intense research. These isozymes are generallydescribed as 5α-reductase 1 or 2, or type 1 or type 2 5α-reductase.

Compounds reportedly useful for inhibiting 5α-reductase are generallysteroid derivatives such as the azasterolds in Rasmusson, et al., J.Med. Chem., 29, (11), 2298-2315 (1986); and benzoylaminophenoxy-butanoicacid derivatives such as those disclosed in EPO 291 245.

European Patent Application 0532190 discloses certain benzo f!quinolinones as 5-α-reductase inhibitors. Certain Indole derivativeshaving steroid 5-α-reductase inhibitory activity are generally disclosedby International Patent Application No. PCT/EP93/00380 (WO/93/17014).

It has now been surprisingly found that the present compounds are morepotent and selective inhibitors of a single isozyme of humantestosterone 5α-reductase (i.e. 5α-reductase-1) which leads to thetherapeutic advantages that the compounds are more efficacious and thatthey can be administered at lower doses, in particular for the treatmentof male pattern baldness which is known to be primarily responsible forhairloss in the human scalp as well as female hirsutism, acne vulgaris,seborrhea and prostatic cancer.

The present Invention provides compounds of the formula: ##STR3## andthe pharmaceutically acceptable base salts thereof, wherein R is --CO₂R¹² where R¹² is H or a biolabile ester-forming group, or R istetrazol-5-yl,

and either (a) R¹ is ##STR4## and R² is F, Cl, Br, I, CH₃ or CF₃ or (b)R¹ is C₃ -C₆ alkyl and R² is C₂ -C₄ alkyl.

Alkyl groups containing three or more carbon atoms may be straight- orbranched-chain.

The term "biolabile ester-forming group" is well understood in medicinalchemistry as meaning a group which forms an ester which can be readilycleaved in vivo to liberate the corresponding compound of the formula(I) where R is --CO₂ H. A number of such ester groups are well-known,for example In the penicillin area or in the case of theangiotensin-converting enzyme (ACE) inhibitor antihypertensive agents.

The compounds of the formula (I) when R¹² is a biolabile ester-forminggroup are not only useful as pro-drugs to provide compounds of theformula (I) wherein R is --CO₂ H in vivo following oral administration,but are also useful as intermediates for the preparation of compounds ofthe formula (I) where R is --CO₂ H.

The suitability of any particular ester-forming group for this purposecan be assessed by conventional in vitro or In vivo enzyme hydrolysisstudies.

Examples of biolabile ester-forming groups are alkyl, alkanoyloxyalkyl(including alkyl, cycloalkyl or aryl substituted derivatives thereof),arylcarbonyloxyalkyl (including aryl substituted derivatives thereof),aryl, arylalkyl, indanyl and haloalkyl: wherein alkanoyl groups havefrom 2 to 8 carbon atoms, alkyl and haloalkyl groups have from 1 to 8carbon atoms and aryl means phenyl or naphthyl, both of which may beoptionally substituted by C₁ -C₄ alkyl, C₁ -C₄ alkoxy or halo. Alkyl,haloalkyl, alkanoyl and alkoxy groups can, where appropriate, bestraight- or branched-chain.

Specific examples of biolabile ester-forming groups are C₁ -C₆ alkyl(e.g. methyl, ethyl, n-propyl, isopropyl), benzyl,1-(2,2-diethylbutyryloxy)ethyl, 2-ethylproplonyloxymethyl,1-(2-ethylproplonyloxy)ethyl, 1-(2,4-dimethylbenzoyloxy)ethyl,a-benzoyloxybenzyl, 1-(benzoyloxy)ethyl,2-methyl-I-propionyloxy-1-propyl, 2,4,6-trimethylbenzoyloxymethyl,1-(2,4,6-trimethyl-benzoyloxy)ethyl, pivaloyloxymethyl, phenethyl,phenpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl,4t-butylphenyl and 5-indanyl.

The pharmaceutically acceptable base salts of the compounds of theformula (I) are formed from suitable bases which form non-toxic saltsand examples thereof are the aluminium, calcium, lithium, magnesium,potassium, sodium, zinc, N-benzyl-N-(2-phenylethyl)amine,1-adamantylamine and diethanolamine salts.

Preferred base salts are the sodium, potassium,N-benzyl-N-(2-phenylethyl)amine and 1-adamantylamine salts. Sodium saltsare the most preferred.

For a review on suitable pharmaceutical salts see Berge et al, Pharm.Sci., 66, 1-19 (1977).

In the above definitions relating to the compounds of the formula (I):

Preferably R is --CO₂ H.

Preferably R¹, when alkyl, is C₃ -C₄ alkyl, more preferably R¹ is C₄alkyl, and yet more preferably R¹ is n-butyl.

Preferably, when R¹ is aryl, R² is F, Cl, Br or I, more preferably Cl.

Preferably R², when alkyl, is C₂ or C₃ alkyl, most preferably ethyl orn-propyl.

A compound of the formula (I) may contain one or more asymmetric carbonatom(s) and therefore exist in two or more stereoisomeric forms. Thepresent invention Includes the individual stereoisomers of the compoundsof the formula (I) and mixtures thereof, together, where appropriate,with all the tautomeric forms of the compounds of the formula (I).Separation of diastereoisomers may be achieved by conventionaltechniques, e.g. by fractional crystallisation, chromatography orH.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) ora suitable salt or derivative thereof. An Individual enantiomer of acompound may also be prepared from a corresponding optically pureIntermediate or by resolution, such as by H.P.L.C. of a racemate using asuitable chiral support or by fractional crystallisation of thediastereoisomeric salts formed by reaction of a racemate with a suitableoptically active base.

The compounds of formula (I) provided by the Invention may be preparedby the following methods:

1) The compounds of the formula (I) where R is --CO₂ H and R¹ and R² areas previously defined for a compound of the formula (I) may be preparedby cleavage of an ester of the formula: ##STR5## where R⁴ is a suitableester-forming group and R¹ and R² are as previously defined for acompound of the formula (I).

A plethora of suitable ester-forming groups that may be cleaved toprovide the corresponding carboxylic acid are known to the skilledperson, see, e.g., T. W. Greene, "Protective Groups in OrganicSynthesis", Wiley-lnterscience (1981).

Where R⁴ is an ester-forming group that may be removed by hydrolysis,e.g. a biolabile ester-forming group as previously defined for R¹² (suchas C₁ -C₆ alkyl), the hydrolysis may be carried out under acidic orbasic conditions, e.g. using an aqueous solution of either a suitablemineral acid or a suitable inorganic base. Preferably the hydrolysis iscarried out under basic conditions.

In a typical hydrolysis procedure, an ester of the formula (II) istreated with an aqueous solution of a suitable base, e.g. sodium orpotassium hydroxide, In the presence of a suitable organic co-solvent,e.g. tetrahydrofuran or a C₁ -C₄ alkanol (e.g. methanol or ethanol) or acombination thereof. The hydrolysis is typically carried out at fromroom temperature to the reflux temperature and preferably at roomtemperature. The product is obtained as a base salt which may beconverted to the carboxylic acid by acidification in the work-upprocedure.

Where R⁴ is an ester-forming group that may be removed by reduction,e.g. benzyl, the reduction may be carried out by catalytic hydrogenationusing, e.g. palladium-on-charcoal, as the catalyst.

The compounds of the formula (II) may be prepared by esterification of acompound of the formula (I) where R is --CO₂ H with an alcohol of theformula R⁴ OH where R⁴ is as previously defined for this method.

The reaction may be carried out under classical esterificationconditions such as by using an excess of the alcohol and with acidcatalysis, e.g. using sulphuric acid or p-toluenesulphonic acid, at fromroom temperature to the reflux temperature. The water generated duringthe reaction may be removed by azeotropic distillation or by the use ofa dehydrating agent or a molecular sieve.

The esterification may also be carried out by reacting the acid with thealcohol in the presence of a suitable dehydrating agent, e.g.dicyclohexylcarbodilmide or diethylazodicarboxylate/triphenylphosphine(see O. Mitsunobu, Synthesis, 1981, 1).

Alternatively the esterification may be carried out by first forming anactivated ester or imidazolide derivative of the carboxylic acid,followed by reaction of the activated ester or imidazolide in situ withthe alcohol of the formula R⁴ OH. An activated ester may be formed byreacting the carboxylic acid with 1-hydroxybenzotriazole in the presenceof a suitable dehydrating agent, e.g.1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide, and in a suitablesolvent, e.g. dichloromethane, at room temperature. An imidazolide maybe formed by reacting the carboxylic acid with 1,1'-carbonyidilmidazolein a suitable solvent, e.g. dichloromethane, at room temperature.

2) The compounds of the formula (I) where R is --CO₂ H and R¹ and R² areas previously defined for a compound of the formula (I) may be preparedby hydrolysis of a compound of the formula: ##STR6## where R⁵ and R⁶ areeach Independently selected from H and C₁ -C₄ alkyl and R¹ and R² are aspreviously defined for a compound of the formula (I).

The hydrolysis may be carried out under acidic or basic conditions, e.g.using an aqueous solution of either a suitable mineral acid (e.g.hydrochloric or sulphuric acid) or a suitable inorganic base (e.g.sodium or potassium hydroxide), at from room temperature to the refluxtemperature. When basic hydrolysis conditions are used the product isobtained as a base salt which may be converted to the carboxylic acid byacidification in the work-up procedure.

3) The compounds of the formula (I) wherein R is --CO₂ H and R¹ and R²are as previously defined for a compound of the formula (I) may beprepared by hydrolysis of a compound of the formula: ##STR7## where R¹and R² are as previously defined for a compound of the formula (I) andR⁷ is H or C₁ -C₄ alkyl.

The hydrolysis may be carried out under acidic or basic conditions, e.g.using an aqueous solution of either a suitable acid (e.g. hydrochloricor acetic acid) or a suitable inorganic base (e.g. sodium or potassiumhydroxide), at from room temperature to the reflux temperature. Whenbasic hydrolysis conditions are used the product is obtained as a basesalt which may be converted to the carboxylic acid by acidification inthe work-up procedure.

4) The compounds of the formula (I) where R is --CO₂ H and R¹ and R² areas previously defined for a compound of the formula (I) may be preparedby hydrolysis of a compound of the formula: ##STR8## where R¹ and R² areas previously defined for a compound of the formula (I).

The hydrolysis may be carried out under acidic or basic conditions, e.g.using an aqueous solution of either a suitable acid (e.g. hydrochloricor sulphuric acid) or a suitable inorganic base (e.g. sodium orpotassium hydroxide), at from room temperature to the refluxtemperature. When basic conditions are used hydrogen peroxide mayoptionally be present and also the product is obtained as a base saltwhich may be converted to the carboxylic acid by acidification In thework-up procedure.

5) The compounds of the formula (I) where R is --CO₂ H and R¹ and R² areas previously defined for a compound of the formula (I) may be preparedby acidic hydrolysis of a compound of the formula: ##STR9## where R¹ andR² are as previously defined for a compound of the formula (I) and R⁸and R⁹ taken together represent ethylene, said ethylene being optionallysubstituted by phenyl or C¹ -C₄ alkyl (preferably methyl). Preferably R⁸and R⁹ taken together represent --CH₂ C(CH₃)₂ --.

The hydrolysis may be carried out using an aqueous solution of asuitable acid such as hydrochloric acid at from room temperature to thereflux temperature.

6) All the compounds of the formula (I) may be prepared by alkylation ofa base salt (i.e. the N-deprotonated form) of a compound of the formula:##STR10## where R¹ and R² are as previously defined for a compound ofthe formula (I), with a compound of the formula: ##STR11## or a basesalt thereof, or with a base salt of a compound of the formula Z(CH₂)₃--CO₂ H, where Z is a suitable leaving group, e.g. halo (preferablybromo or iodo), methanesulphonyloxy or p-toluenesulphonyloxy.

The preferred base salts of the compounds of the formula Z(CH₂)₃ --CO₂ Hinclude the alkali metal and alkaline earth metal salts, e.g. the sodiumand potassium salts.

The preferred base salts of the compounds of the formulae (VII) and(VIII) include the alkali metal salts, e.g. the sodium and potassiumsalts.

The reaction may be performed by initial deprotonation of a compound ofthe formula (VII) with a suitable base, e.g. sodium hydride or potassiumcarbonate, followed by reaction of the resulting anion with a compoundof the formula (VIII) or a base salt thereof, or with a base salt of acompound of the formula Z(CH₂)₃ --CO₂ H, as appropriate. The reactionmay be carried out in a suitable solvent, e.g. N,N-dimethylformamide,tetrahydrofuran or 2-butanone, at from 0° C. to the reflux temperature.

Alternatively the reaction may be carried out under phase transferconditions using a suitable base such as sodium or potassium hydroxide.

The compound of the formula (I) may be obtained as a base salt which canbe converted to the carboxylic acid or NH-tetrazole, as appropriate, byacidification in the work-up procedure.

7) The compounds of the formula (I) where R is --CO₂ H and R¹ and R² areas previously defined for a compound of the formula (I) may be preparedby oxidative cleavage of a compound of the formula: ##STR12## where Z¹is --CH═CH₂ or --C.tbd.CH and R¹ and R² are as previously defined for acompound of the formula (I).

The reaction may be carried out by ozonolysis or by treatment withaqueous potassium permanganate solution.

8) The compounds of the formula (I) wherein R is --CO₂ H and R¹ and R²are as previously defined for a compound of the formula (I) may beprepared by oxidation of a compound of the formula: ##STR13## where R¹and R² are as previously defined for a compound of the formula (I). Asuitable oxidising agent for this purpose is chromium trioxide inpyridine.

9) All the compounds of the formula (I) may be prepared by reaction of acompound of the formula: ##STR14## where R is as previously defined fora compound of the formula (I), with a) a compound of the formula:##STR15## where R¹ and R² are as previously defined for a compound ofthe formula (I). In a typical procedure the ketal of the formula (XII)and the compound of the formula (XI) are heated together under reflux ina suitable organic solvent, e.g. toluene, in the presence of a catalyticamount of a suitable acid, e.g. p-toluenesulphonic acid. Preferably adimethyl ketal is used and the reaction is carried out in a Dean-Starkapparatus;

b) a compound of the formula: ##STR16## where R¹ and R² are aspreviously defined for a compound of the formula (I). The preferred C₁-C₄ alkyl group In the compounds of the formula (XIII) is methyl. In atypical procedure the compounds of the formula (XI) and (XIII) areheated together in a suitable organic solvent, e.g. toluene, withmercury (II) catalysis, e.g. using mercury (II) chloride;

c) a compound of the formula: ##STR17## where R¹ and R² are aspreviously defined for a compound of the formula (I). In a typicalprocedure the compounds of the formulae (XI) and (XIV) are heatedtogether under reflux in a suitable organic solvent, e.g. toluene, Inthe presence of a suitable acid catalyst, e.g. hydrochloric acid orsulphuric acid, and preferably in a Dean-Stark apparatus; or

d), for compounds of the formula (I) where the R¹ moiety is alkyl havinghydrogen atom on the α-carbon atom with 20 respect to its position ofattachment to the 1,3- benzodioxolane ring, an enol ether derivative ofa compound of the formula: ##STR18## where R¹ and R² are as previouslydefined for a compound of the formula (I) but with the above conditionapplying in respect of the definition of R¹. The reaction is typicallycarried out in a suitable organic solvent, e.g. toluene, in the presenceof an acid catalyst, e.g. p-toluenesulphonic, hydrochloric or sulphuricacid, at from room temperature to the reflux temperature of the solvent.

Suitable enol ether derivatives for use in this procedure (d) may bederived from a compound of the formula (XIVA) by reaction with asuitable tri(C₁ -C₄ alkyl) orthoformate, e.g. trimethyl orthoformate, inthe presence of an acid catalyst, e.g. p-toluenesulphonic acid.

To prepare a compound of the formula (I) any one of methods (9)(a) to(d) may also be carried out using a suitable base (e.g. sodium) salt ofa compound of the formula (XI), e.g. where R is --CO₂ H, a carboxylatesalt, the reaction being followed by an acidification step in thework-up procedure, as appropriate. The starting materials of the formula(XI) may be prepared by acidic hydrolysis of a compound of the formula:##STR19##

where R¹⁰ and R¹¹ are each independently selected from H and Cl and arepreferably both Cl, and R is as previously defined for a compound of theformula (I).

In a typical procedure the hydrolysis is carried out using aqueousacetic acid and the reaction is heated under reflux.

The compounds of the formula (XV) may be prepared by similar methods tothose described herein for the preparation of the compounds of theformula (I).

10) The compounds of the formula (I) where R is tetrazol-5-yi and R¹ andR² are as previously defined for a compound of the formula (I), may beprepared by reaction of a compound of the formula (V) where R¹ and R²are as previously defined for a compound of the formula (I), with asuitable azide, e.g. an alkali metal azide (preferably sodium azide) ortrimethylsilylazide in the presence of fluoride ion. The reaction istypically carried out in a suitable solvent, e.g.N-methyl-2-pyrrolidinone, at from 100 to 150° C. (see Synthesis, 1987,1133).

11) The compounds of the formula (I) where R is tetrazol-5-yl and R¹ andR² are as previously defined for a compound of the formula (I), may beprepared by deprotection of a compound of the formula: ##STR20## whereR¹ and R² are as previously defined for a compound of the formula (I).

In a typical procedure the deprotection is carried out using a suitablebase, e.g. sodium hydroxide, and in a suitable solvent, e.g.tetrahydrofuran methanol, at about room temperature.

A compound of the formula (XVI) may be prepared by a two-step procedurestarting from the corresponding compound of the formula (I) where R is--CO₂ H and R¹ and R² are as previously defined for a compound of theformula (I). In the first step the carboxylic acid is reacted with3-aminopropanitrile under standard peptide coupling conditions, e.g.using 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide and1-hydroxybenzotriazole in a suitable solvent such as dichloromethane, toprovide a compound of the formula: ##STR21## where R¹ and R² are aspreviously defined for a compound of the formula (I).

A compound of the formula (XVII) may be converted to a compound of theformula (XVI) by treatment with trimethylsilylazide,diethylazodicarboxylate and triphenylphosphine in a suitable solvent,e.g. tetrahydrofuran, at room temperature.

This method of converting a compound of the formula (I) where R is --CO₂H to a compound of the formula (I) where R is tetrazol-5-yl is based ona literature procedure that is described in J. Org. Chem., 56, 2395(1991).

The compounds of the formulae (II), (III), (IV), (V), (VI), (IX), (X),(XVI) and (XVII) can all be prepared by appropriate alkylation of a basesalt of a compound of the formula (VII) by a similar procedure to thatdescribed in method (6) for the preparation of the compounds of theformula (I).

All of the above reactions and the preparations of novel startingmaterials used in the preceding methods are conventional and appropriatereagents and reaction conditions for their performance or preparation aswell as procedures for isolating the desired products will be well knownto those skilled in the art with reference to literature precedents andthe Examples and Preparations hereto.

A pharmaceutically acceptable base salt of a compound of the formula (I)may be readily prepared by mixing together solutions of a compound ofthe formula (I) and the desired base. The salt may precipitate fromsolution and be collected by filtration or may be recovered byevaporation of the solvent.

The compounds of the formula (I) are steroid 5α-reductase inhibitors andtherefore they are useful in the curative or prophylactic treatment ofdiseases or conditions such as acne vulgaris, alopecia, seborrhoea,female hirsutism, benign prostatic hypertrophy and male patternbaldness.

The compounds of the formula (I) are also useful for the treatment ofhuman prostate adenocarcinomas.

The compounds of the formula (I) may be tested in vitro for testosterone5α-reductase inhibitory activity using prostate tissue from rats orhumans as follows:

(a) The compounds of the formula (I) may be tested for their potency ininhibiting rat testosterone 5α-reductase using ventral prostate tissuefrom male rats. In determining inhibitory potency against rat prostatic5α-reductase the following procedure was employed:

Rat prostates were minced into small pieces. The tissue was homogenisedin Buffer A (20 mM sodium phosphate, pH 6.5, buffer containing 0.32Msucrose and 1 mM dithiothreltol) with a Brinkman Polytron (KinematicaGmBH, Luzern), and then homogenised with a motor-driven (1000 rpm)Potter Elvehjem (teflon-to-glass) homogeniser. Prostate particles wereobtained by centrifugation at 105,000 G for 60 minutes. The pellet waswashed in 4 volumes of

Buffer A and recentrifuged at 105,000 G. The resulting pellet wasdispersed in Buffer A (1 ml per g of prostate tissue originally used)with a motor-driven Potter Elvehiem homogeniser as described above. Theparticulate suspension was stored as 1 ml samples at -70° C.

The following components, dissolved in Buffer B (40 mM sodium phosphatebuffer, pH 6.5), were added to a test tube: 500 l of ³ H!-testosterone(1 μci, 1 nmol; Du Pont, NEN Research Products, Stevenage, U.K.), 100 μlof 0.5 mM NADPH, a compound of the formula (I) dissolved in 5 μl ofdimethyl sulphoxide, and Buffer B to give a final reaction volume of 1ml. The mixture was warmed to 37° C. and the reaction started byaddition of an aliquot of prostate particulate suspension. The reactionmixture was incubated at 37° C. for 30 minutes and then quenched byaddition with vigorous mixing of 2 ml of ethyl acetate containing 20 μgeach of testosterone and 5α-dihydrotestosterone as carriers. The aqueousand organic layers were separated by centrifugation at 2000 G for 10minutes. The organic layer was transferred to a second test tube andevaporated to dryness under nitrogen. The residue was dissolved in 50-80μl of absolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E.Merck, Darmstadt, Germany) and developed in dichloromethane:acetone(185:15).

The radiochemical content in the bands of the substrate (testosterone)and the product (5α-dihydrotestosterone) were determined with a RITARadio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). Thepercent of recovered radiolabel converted to 5α-dihydrotestosterone wascalculated and used to determine enzyme activity. All incubations wereconducted so that no more than 15% of substrate (testosterone) wasconverted to product.

The experimentally obtained data for a range of inhibitor concentrationswas omputer fitted to a sigmoidal dose-response curve and concentrationsof compound giving 50% inhibition of 5α-reductase activity (IC₅₀ 's)were calculated using a SIGFIT program (De Lean, A., Munson, P. J. andRodbard, D., American Journal of Physiology, 235, E97 (1978)).

(b) (i) The compounds of the formula (I) may be tested for their potencyin inhibiting human testosterone 5αreductase-2 using tissue fromhyperplastic human prostates. In determining inhibitory potency againsthuman prostatic 5α-reductase-2 the following procedure was employed:

Frozen human prostate tissue was puiverised in liquid nitrogen using asteel mortar and pestle. The powdered tissue was homogenised in 4volumes of Buffer A (20 mM sodium phosphate, pH 6.5, containing 0.32Msucrose, 1 mM dithiothreitol and 50 μM NADPH) with an Ultra-Turraxhomogeniser (Janke and Kunkel GmBH & Co., Staufen I.BR., Germany). Thehomogenate was centrifuged at 500 G for 5 minutes to remove largeparticles of tissue, and the supernatant was then centrifuged at 100,000G for 1 hour. The resulting pellet was dispersed in Buffer A (1 ml per gof prostate tissue originally used) with the Ultra-Turrax homogeniser.This particulate preparation was then filtered through 2 layers ofcheesecloth and the filtrate was stored as 2 ml samples at -70° C.

The following components, dissolved in Buffer B (25 mM citrate phosphatebuffer, pH 5.2), were added to a test tube: 100 μl of ³ H!-testosterone(1 μCi, 1nmol; Du Pont, NEN Research Products, Stevenage, U.K.), 100 μlof NADPH regeneration system (5 mM NADPH, 50 mM glucose 6-phosphate, 5units/ml glucose 6-phosphate dehydrogenase), a compound of the formula(I) dissolved in 5 μl of dimethyl sulphoxide, and Buffer B to give afinal reaction volume of 1 ml. The mixture was warmed to 37° C. and thereaction started by addition of an aliquot of prostate particulatesuspension. The reaction mixture was incubated at 37° C. for 30 minutesand was then quenched by addition, with vigorous mixing, of 2 ml ofethyl acetate containing 20 μg each of testosterone and5α-dihydrotestosterone as carriers. The aqueous and organic layers wereseparated by centrifugation at 2000 G for 10 minutes. The organic layerwas transferred to a second test tube and evaporated to dryness undernitrogen. The residue was dissolved in 50-80 μl of absolute ethanol,spotted onto a silica gel 60 F254 TLC plate (E. Merck, Darmstadt,Germany) and developed in dichloromethane:acetone (185:15).

The radiochemical content in the bands of the substrate (testosterone)and the product (5α-dihydrotestosterone) were determined with a RITARadio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). Thepercent of recovered radiolabel converted to 5α-dihydrotestosterone wascalculated and used to determine enzyme activity. All incubations wereconducted so that no more than 15% of substrate (testosterone) wasconverted to product.

The experimentally obtained data for a range of inhibitor concentrationswas computer fitted to a sigmoldal dose-response curve andconcentrations of compound giving 50% inhibition of 5α-reductaseactivity (IC₅₀ 's) were calculated using a SIGFIT program (De Lean, A.,Munson, P. J. and Rodbard, D., American Journal of Physiology, 235 E97(1978)).

(ii) The compounds of the formula (I) may be tested for potency ininhibiting steroid 5α-reductase activity in human prostateadenocarcinomas using cell lines DU145 and HPC36M. In determininginhibitory potency against 5α-reductase the following procedure wasemployed:--Human prostate adenocarcinoma cell lines were grown inDulbecco's Modified Eagles medium (DMEM) containing 5% serum. The cellswere recovered from the medium by centrifugation, washed in serum-freeDMEM and suspended at 5-10×10⁶ cells/ml. in serum-free medium.

The following components were added to a test tube: 10 μl of ³H!-testosterone (1 μCi, 20 pmol) dissolved in ethanol (Du Pont, NENResearch Products, Stevenage, U.K.) and 5 μl of an ethanol solution of acompound of the formula (I). The ethanol was evaporated under nitrogenand the testosterone and the compound were redissolved in 0.25 ml ofserum-free medium containing 0.25 μmol NADPH. The mixture was warmed to37° C. and the reaction started by addition of 0.25 ml of cellsuspension (1.2-2.5×10⁶ cells). The reaction mixture was incubated at37° C. for 2 hours and then quenched by addition, with vigorous mixing,of 1.5 ml of ethyl acetate containing 20 μg each of testosterone and5α-dihydrotestosterone as carriers.

The aqueous and organic layers were separated by centrifugation at 2000G for 10 minutes. The organic layer, containing testosterone and itsmetabolites, was transferred to a second test tube and evaporated todryness under nitrogen. The residue was dissolved in 50-80 μl ofabsolute ethanol, spotted onto a silica gel 60 F254 TLC plate (E. Merck,Darmstadt, Germany) and developed in dichloromethane: acetone (185:15).

The radiochemical content in the bands of the substrate (testosterone)and the product (5α-dihydrotestosterone) was determined with a RITARadio TLC Analyser (Raytest Instruments Ltd., Sheffield, U.K.). Thepercentage of recovered radiolabel converted to 5α-dihydrotestosteronewas calculated and used to determine enzyme activity. All incubationswere conducted so that no more than 15% of substrate (testosterone) wasconverted to product.

The experimentally obtained data for a range of inhibitor concentrationswas computer fitted to a sigmoidal dose-response curve andconcentrations of compound giving 50% inhibition of 5α-reductaseactivity (IC₅₀ 's) were calculated using a SIGFIT program (De Lean, A.,Munson, P. J. and Rodbard D., American Journal of Physiology, 235, E97(1978)).

The compounds of the formula (I) may be tested in vitro for humantestosterone 5α-reductase-1 inhibitory activity using cloned humantestosterone 5α-reductase-1 according to the procedure described inProc. Natl. Acad. Sci. USA, 87, 3640 (1990).

For human use, the compounds of the formula (I) can be administeredalone, but will generally be administered in admixture with apharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. For example, theycan be administered orally in the form of tablets containing suchexcipients as starch or lactose, or in capsules or ovules either aloneor in admixture with excipients, or in the form of elixirs, solutions orsuspensions containing flavouring or colouring agents. They can beinjected parenterally, for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances,for example, enough salts or glucose to make the solution isotonic withblood.

For oral and parenteral administration to human patients, the dailydosage level of the compounds of the formula (I) will be from 0.01 to 20mg/kg (in single or divided doses) and preferably will be from 0.1 to 10mg/kg except for the treatment of human prostate adenocarcinomas wheredoses of up to 20 mg/kg may be used. Thus tablets or capsules of thecompounds will contain from 5 mg to 0.5 g of active compound foradministration singly or two or more at a time, as appropriate. Thephysician in any event will determine the actual dosage which will bemost suitable for an individual patient and it will vary with the age,weight and response of the particular patient. The above dosages areexemplary of the average case; there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Alternatively, the compounds of the formula (I) can be administered inthe form of a suppository or pessary, or they may be applied topicallyin the form of a lotion, solution, cream, ointment or dusting powder.For example, they can be incorporated into a cream consisting of anaqueous emulsion of polyethylene glycols or liquid paraffin; or they canbe incorporated, at a concentration between 1 and 10%, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilizers and preservatives as may be required.

The compounds of the formula (I) may also be administered together withan α-antagonist (e.g. prazosin or doxazosin), an antiandrogen (e.g.flutamide) or an aromatase inhibitor (e.g. atamestane), particularly forthe curative or prophylactic treatment of benign prostatic hypertrophy.

The following Examples illustrate the preparation of the compounds ofthe formula (I):

EXAMPLE 1 4- 3-(2,2-p-Chlorophenyl-1,3-benzodioxolan-5-yl!carbonyl)-2-methylindol-1-yl!butanoicacid. ##STR22##

A solution of ethyl-4- 3-(2,2-p-chlorophenyl-1,3-benzodioxolan-5-yl!carbonyl)-2-methylindol-1-yl!butanoate(685 mg) (see Example 4) in tetrahydrofuran (10 ml) and methanol (10 ml)was treated with 2N aqueous sodium hydroxide (10 ml) and stirredovernight (25° C.). The mixture was concentrated in vacuo, cooled in anice bath and acidified with 2N aqueous hydrochloric acid. The acid phasewas extracted with ethyl acetate (50 ml), the organic extract dried(MgSO₄), filtered and evaporated in vacuo to give the title compound asa yellow foam (550 mg). Found: C,66.84; H,4.59; N,2.17; C₃₃ H₂₅ Cl₂ NO₅requires: C,67.58; H,4.30; N,2.39%. m/z=588(m+) and 586(m+). ¹ H-NMR(CDCl₃):δ=2.15(m,2H), 2.50(t,2H), 2.60(s,3H), 4.25(t,2H), 6.85(d, 1H),7.10(t,1H), 7.25(t,1H), 7.35-7.55(m,12H) ppm.

EXAMPLE 2 4- 3-( 2-butyl-(4-n-propylphenyl)-1.3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoic acid

The procedure of Example 1 was followed but using ethyl-4- 3-(2-butyl-2(4-n-propylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoate(from Example 5) as the starting material to give the title compound asa white foam: Found: C,74.94; H,6.81; N,2.33; C₃₄ H₃₇ NO₅ requires:C,75.67; H,6.91; N,2.60%. m/z=540(m+). ¹ H-NMR (CDCl₃):δ=0.95(t,3H),1.00(t,3H), 1.30-1.55(m,4H), 1.65(m,2H) 2.20(m,2H), 2.30(m,2H),2.55(t,2H), 2.60(t,2H), 2.65(s,3H), 4.25(t,2H), 6.80(d, 1H), 7.10(t,1H), 7.20-7.55(m,9H) ppm.

EXAMPLE 3 4- 3-(2-butyl-2-(4-ethylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoicacid

The procedure of Example 1 was followed but using ethyl-4- 3-(2-butyl-2-(4-ethylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoate(from Example 6) as starting material to give the title compound as awhite foam: Found: C,74.41; H,6.88; N,2.36; C₃₃ H₃₅ NO₅.1/2H₂ O requiresC,74.12; H,6.79; N,2.62%. m/z=526(m+1). ¹ H-NMR (CDCl₃): δ=0.90(t,3H),1.25(t,3H), 1.28-1.50(m,4H), 2.15-2.20(m,2H), 2.20-2.28(m,2H),2.49(t,2H), 2.60(s,3H), 2.65(q,2H), 4.25(t,2H) 6.80(d, 1H), 7.10(t, 1H),7.20-7.55(m,9H) ppm.

EXAMPLE 4 Ethyl-4- 3-(2.2-p-chlorophenyl-1.3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoate ##STR23##

A suspension of 3-(2,2-p-chlorophenyl-1,3-benzodioxolan-5-yl!carbonyl)2-methylindole (9.0g) (see Preparation 1) in 2-butanone was treated with anhydrouspotassium carbonate (24.84 g) and ethylbromobutyrate (3.35 ml). Themixture was mechanically stirred and heated under reflux for 16 hours.After cooling, the mixture was filtered and the filtrate evaporated toan oil. Flash column chromatography SiO₂ (3:1 hexane/ethylacetate) gavethe title compound as a white foam (6.0 g). m/z=614 (m+) and 616 (m+). ¹H-NMR (CDCl₃): δ=1.30(t,3H), 2.15(m,2H), 2.40(t,2H), 2.60(s, 3H),4.15(q,2H),4.25(t,2H),6.90(d,1 H), 7.1 0(t,1 H),7.20(t,1H),7.35-7.55(m,12H) ppm.

EXAMPLE 5 Ethyl-4-3-(r2-butyl-2-W4-n-propylphenyl)-1.3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoate##STR24##

A mixture of ethyl-43-(3,4-dihydroxybenzoyl)2-methylindol-1-yl!butanoate (320 mg) (seePreparation 2) and 1,1-dimethoxy-1-(4-n-propylphenyl)pentane (580 ml)(see Preparation 5) in toluene (40 ml) was treated under reflux (1 hour)in a Dean and Stark apparatus. The first few millilitres of toluene werecollected and removed, the reaction cooled (60° C.) andp-toluenesulphonic acid (30 mg) added to the reaction mixture. Themixture was heated under reflux (16 hour), cooled and evaporated. Flashcolumn chromatography SiO₂ (3:1 hexane/ethyl acetate) gave the titlecompound as a clear oil (380 mg). m/z=554 (m+). ¹ H-NMR (CDCl₃):δ=0.90(t,3H), 1.25(t,3H), 1.28(t,3H), 1.30-1.50(m,6H) 2.10(m,2H),2.20-2.30(m,2H), 2.40(t,2H), 2.60(s,3H), 2.65-2.75(m,2H), 4.15(q, 2H),4.20(t,2H), 6.80(d,1H), 7.07(t,1H), 7.17-7.40(m,7H), 7.50(d,2H) ppm.

EXAMPLE 6Ethyl-4-r3-(r2-butyl-2(4-ethylphenyl)-31-benzodioxolan-5-yllcarbonyl)2-methylindol-1-yl!butanoate

The procedure of Example 5 was followed but using1,1-dimethoxy-1-(4-ethylphenyl)pentane, in place of1,1-dimethoxy-1-(4-n-propylphenyl)pentane, to give the title compound asa clear oil. m/z=554(m+). ¹ H-NMR (CDCl₃): δ=0.90(t,3H), 1.25(t,3H),1.28(t,3H), 1.30-1.50(m,4H 2.15-2.20(m,2H), 2.20-2.28(m,2H), 2.49(t,2H),2.60(s,3H), 2.65(q,2H), 4.15(q,2H), 4.25(t,2H), 6.80(d,1 H), 7.10(t,1H), 7.20-7.55(m,7H), 7.60(d,2H) ppm.

PREPARATION 1 3-(2.2-p-chlorophenyl-1.3-benzodioxolan-5-yllcarbonyl)2-methylincdole##STR25##

2,2-p-chlorophenyl-1,3-benzodioxolan-5-carboxylic acid (9.70 g) (fromPreparation 3) was suspended in dichloromethane (200 ml) and treatedwith oxalyl chloride (2.6 ml) and dimethylformamide (7 drops). Themixture was stirred (1 hour) until homogenous and then evaporated to acream solid which was azeotroped (×3) with toluene to remove oxalylchloride. The crude acid chloride was used directly in the next stage.

A solution of 2-methylindole (6.56 g) in toluene (50 ml) was treatedwith methylmagnesium iodide (16.7 ml of 3.0M solution in diethyl ether)and cooled to -78° C. Pyridine (4.0 ml) was added followed byportionwise addition of the acid chloride prepared as above; the mixturewas allowed to warm to room temperature overnight and then partitionedbetween ethyl acetate and saturated aqueous ammonium chloride solution.The organic layer was separated and concentrated slightly. Upon standingovernight the title compound crystallised as a pink solid. Filtrationand trituration with 9:1 hexane/ethyl acetate gave the title compound asa pale pink powder (9.0g). m/z=500 (m+). ¹ H-NMR (d⁶ -DMSO): δ=2.40(s,3H), 7.00(t,1 H), 7.10-7.40(m,6H), 7.55-7.60(m,8H),11.90(s,br,1 H) ppm.

PREPARATION 2

Ethyl-4 3-(3.4-dihydroxybenzoyl)2-methylindol-1-yl!butanoate ##STR26##

Ethyl-4- 3-(2,2-p-chlorophenyl-1,3-benzodioxolan-5yl!carbonyl)2-methylindol-1-yl!butanoate(4.5 g) was dissolved in glacial acetic acid (80 ml) and water (70 ml)and heated under reflux for 8 hours. The reaction mixture was cooled,evaporated in vacuo and the residue partitioned between ethyl acetateand saturated aqueous sodium bicarbonate. The organic layer wasseparated and washed (×3) with saturated aqueous sodium bicarbonate. Theorganic layer was dried (MgSO₄) and evaporated to give the titlecompound as a tan solid (1.52 g). m/z=382(m+1). ¹ H-NMR (CDCl₃):δ=1.10(6,3H), 1.85-1.95(m,2H), 2.35-2.45(m,2H), 2.45(s,3H), 4.00(q,2H),4.25(t,2H), 6.80(d,2H), 6.95-7.40(m,4H), 7.50(d,1H), 9.40(s,br, 2H) ppm.

PREPARATION 3 2,2-p-Chlorophenyl-1,3-benzodioxolan-5-carboxylic acid##STR27##

A mixture of 4,4'-dichlorobenzophenone dimethylketal (8.71 g )(Preparation 4) and 3,4-dihydroxymethylbenzoate (5.19 g) in toluene (200ml) was heated under reflux (1 hour) in a Dean and Stark apparatus.After cooling (60° C.), p-toluenesulphonie acid (50 mg) was added andthe mixture heated under reflux overnight. Upon cooling, the mixture wasevaporated to a red gum which was dissolved in methanol (60 ml) andtetrahydrofuran (60 ml) at 0°; 2N aqueous sodium hydroxide (60 ml) wasadded and the mixture stirred overnight. Careful evaporation of themethanol and tetrahydrofuran was followed by addition of 2N aqueoushydrochloric acid until the mixture became acidic. The resultantprecipitate was collected and dried to give the title compound as anoff-white powder (7.15 g). m/z=386 (m+) and 388 (m+). ¹ H-NMR (d⁶-DMSO): δ=7.00(d, 1H), 7.40(s, 1H), 7.45-7.55(m,9H) ppm.

PREPARATION 4 4,4'-Dichlorobenzophenone dimethyl ketal ##STR28##

A mixture of 4,4-dichlorobenzophenone (20.0 g), trimethylortholormate(20.0 ml), methanol (200 ml) and p-toluene sulphonic acid (100 mg) washeated under reflux (16 hours). The cooled reaction was evaporated andbasified with a few drops of 30% w/w solution of sodium methoxide inmethanol; at this point the product crystallised out as chunky needles.Filtration gave the title compound as a crystalline solid (22.0g).m/z=296 (m+). ¹ H-NMR (CDCl₃): δ=3.10(s,6H), 7.30(d,4H), 7.40(d,4H) ppm.

PREPARATION 5 1,1-Dimethoxy-1-(4-n-propyl)phenylpentane ##STR29##

A mixture of 1-(4-n-propyl)phenylpentan-1-one (500 mg) (see Preparation6), trimethyl orthoformate (1.1 ml), methanol (20 ml) andp-toluenesulphonic acid (10 mg) was heated under reflux for 16 hours.The cooled reaction mixture was basified (using a few drops of a 30% w/wsolution of sodium methoxide in methanol) and the reaction mixture waspartitioned between water (20 ml) and diethyl ether (20 ml). The etherlayer was separated, washed with brine (20 ml) and dried (MgSO₄) to givethe title compound as a colourless oil (600 mg). ¹ H-NMR (CDCl₃):δ=1.80(t,3H), 0.90-1.02(m,5H), 1.10-1.25(m,2H), 1.60-1.75(m,2H),1.85-1.92(m,2H), 2.60(t,2H), 3.17(s,6H), 7.17(d,2H), 7.36(d,2H) ppm.

PREPARATION 6 1-(4-n-Propyl)phenylpentan-1-one ##STR30##

A solution of n-butyl lithium (1.6N in hexane, 3.65 ml) intetrahydrofuran (10 ml) was cooled to -78° C., treated dropwise with asolution of N-methoxy-N-methyl-4-n-propylbenzamide (1.1 g) (seePreparation 7) in tetrahydrofuran (10 ml) and the solution was allowedto warm to room temperature overnight. The reaction mixture waspartitioned between dichloromethane (50 ml) and 2N aqueous hydrochloricacid (50 ml). The organic layer was separated, dried (MgSO₄) andevaporated to give a yellow oil which was subjected to flashchromatography (silica, eluant=3:1 hexane/ethyl acetate) to give thetitle compound as a clear oil (545 mg). ¹ H-NMR (CDCl₃): δ=0.95(t,6H),1.38-1.49(m,2H), 1.62-1.80(m,4H), 2.65(t,2H), 2.95(t,2H), 7.25(d,2H),7.90(d,2H) ppm.

PREPARATION 7 N-Methoxy-N-methyl-4-n-propylbenzamide ##STR31##

A mixture of 4-n-propylbenzoic acid (10.0 g), 1-hydroxybenzotriazolehydrate (8.20 g), 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (21.5 g) and dichloromethane (1000 ml) was treateddropwise with triethylamine (42.6 ml) and N,O-dimethylhydroxylaminehydrochloride (6.6 g). The mixture was stirred overnight at roomtemperature and then treated with water (700 ml). The organic layer wasseparated, washed with 2N aqueous hydrochloric acid (4×500 ml) and thensaturated aqueous sodium bicarbonate solution (4×500ml). The organicphase was dried (MgSO₄) and concentrated to give the title compound as aclear oil (10.8 g). ¹ H-NMR (CDCl₃): δ=0.95(t,3H), 1.65(m,2H),2.60(t,2H), 3.36(s,3H), 3.58(s,3H), 7.20(d,2H), 7.60(d, 2H) ppm.

PREPARATION 8 1,1 -Dimethoxy-1 -(4-ethylphenyl)pentane

This compound was prepared by the method outlined in Preparation 5 from1-(4-ethylphenyl)pentan-1-one which, in turn, was prepared by methodssimilar to those outlined in Preparations 6 and 7.

We claim:
 1. A compound of formula (I): ##STR32## and thepharmaceutically acceptable base salts thereof, wherein: R is CO₂ R¹²where R¹² is H or a C₁ -C₆ alkyl ester, and either (a) R¹ is ##STR33##and R² is F, Cl, Br, I, CH₃ or CF₃, or (b) R¹ is C₃ -C₆ alkyl and R² isC₂ -C₄ alkyl.
 2. A compound according to claim 1, in which R is CO₂ H.3. A compound according to claim 1, in which R¹ is C₃ -C₄ alkyl.
 4. Acompound according to claim 3, in which R¹ is n-butyl.
 5. A compoundaccording to claim 3 in which R² is ethyl or n-propyl.
 6. A compoundaccording to claim 1 in which, R¹ is ##STR34## and R² is F, Cl, Br or I.7. A compound selected from:4- 3-(2,2-p-chlorophenyl-1,3-benzodioxolan-5-yl!carbonyl)-2-methylindol-1-yl!butanoicacid; 4- 3-(2-butyl-(4-n-propylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoicacid; 4- 3-(2-butyl-2-(4-ethylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoicacid; ethyl-4- 3-(2,2-p-chlorophenyl-1,3-benzodioxolan-5-yl)carbonyl)2-methylindol-1-yl!butanoate;ethyl-4- 3-(2-butyl-2-{4-n-propylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoate;and ethyl-4- 3-(2-butyl-2-(4-ethylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)2-methylindol-1-yl!butanoate,andpharmaceutically acceptable base salts thereof.
 8. A compound accordingto claim 1, wherein said salt is a sodium, potassium,N-benzyl-N-(2-phenylethyl)amine or 1-adamantylamine salt.
 9. A compoundaccording to claim 1, wherein said compound is 4- 3-( 2,2-bis(p-chlorophenyl)-1,3-benzodioxolan-5-yl!carbonyl)-2-methylindol-2!1-yl!butanoic acid;4- 3-(2-butyl-2-(4-n-propylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)-2-methylindol-1-yl!butanoicacid; 4- 3-(2-butyl-2-(4-ethylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)-2-methylindol-1-yl!butanoicacid; ethyl 4- 3-( 2,2-bisp-chlorophenyl)-1,3-benzodioxolan-5-yl)carbonyl)-2-methylindol-1-yl!butanoate;ethyl 4- 3-( 2,!-butyl-2-(4-n-propylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)-2-methylindol-1-yl!butanoate;ethyl 4- 3-( 2,!-butyl-2-(4-ethylphenyl)-1,3-benzodioxolan-5-yl!carbonyl)-2-methylindol-1-yl!butanoategandthe pharmaceutically acceptable salts thereof.